Genomic driven treatment and drug rediscovery in patients with advanced cancer

This thesis focuses on precision oncology, discussing the findings of the Drug Rediscovery Protocol (DRUP) and examining the diverse patient groups treated in this study. In DRUP, an innovative Dutch study, patients with advanced-stage cancer, for whom all available treatment options have been exhausted, are treated with approved targeted therapies, applied beyond there registered indications. The primary goal of DRUP is to improve outcomes for individual patients by implementing a personalized treatment strategy: the right therapy for the right patient at the right time.The printing of this thesis was financially supported by University of Leiden, the Department of Oncology of Leiden University Medical Center, Rockmed and Novartis.LUMC / Geneeskund

Tur\'an Graphs, Stability Number, and Fibonacci Index

The Fibonacci index of a graph is the number of its stable sets. This parameter is widely studied and has applications in chemical graph theory. In this paper, we establish tight upper bounds for the Fibonacci index in terms of the stability number and the order of general graphs and connected graphs. Tur\'an graphs frequently appear in extremal graph theory. We show that Tur\'an graphs and a connected variant of them are also extremal for these particular problems.Comment: 11 pages, 3 figure

Edge effects in a frustrated Josephson junction array with modulated couplings

A square array of Josephson junctions with modulated strength in a magnetic field with half a flux quantum per plaquette is studied by analytic arguments and dynamical simulations. The modulation is such that alternate columns of junctions are of different strength to the rest. Previous work has shown that this system undergoes an XY followed by an Ising-like vortex lattice disordering transition at a lower temperature. We argue that resistance measurements are a possible probe of the vortex lattice disordering transition as the linear resistance $R_{L}(T)\sim A(T)/L$ with $A(T) \propto (T-T_{cI})$ at intermediate temperatures $T_{cXY}>T>T_{cI}$ due to dissipation at the array edges for a particular geometry and vanishes for other geometries. Extensive dynamical simulations are performed which support the qualitative physical arguments.Comment: 8 pages with figs, RevTeX, to appear in Phys. Rev.

Monitoring the T-Cell Receptor Repertoire at Single-Clone Resolution

The adaptive immune system recognizes billions of unique antigens using highly variable T-cell receptors. The αβ T-cell receptor repertoire includes an estimated 10(6) different rearranged β chains per individual. This paper describes a novel micro-array based method that monitors the β chain repertoire with a resolution of a single T-cell clone. These T-arrays are quantitative and detect T-cell clones at a frequency of less than one T cell in a million, which is 2 logs more sensitive than spectratyping (immunoscope), the current standard in repertoire analysis. Using T-arrays we detected CMV-specific CD4+ and CD8+ T-cell clones that expanded early after viral antigen stimulation in vitro and in vivo. This approach will be useful in monitoring individual T-cell clones in diverse experimental settings, and in identification of T-cell clones associated with infectious disease, autoimmune disease and cancer

Critical behavior of the frustrated antiferromagnetic six-state clock model on a triangular lattice

We study the anti-ferromagnetic six-state clock model with nearest neighbor interactions on a triangular lattice with extensive Monte-Carlo simulations. We find clear indications of two phase transitions at two different temperatures: Below $T_I$ a chirality order sets in and by a thorough finite size scaling analysis of the specific heat and the chirality correlation length we show that this transition is in the Ising universality class (with a non-vanishing chirality order parameter below $T_I$). At $T_{KT}(<T_I)$ the spin-spin correlation length as well as the spin susceptibility diverges according to a Kosterlitz-Thouless (KT) form and spin correlations decay algebraically below $T_{KT}$. We compare our results to recent x-ray diffraction experiments on the orientational ordering of CF$_3$Br monolayers physisorbed on graphite. We argue that the six-state clock model describes the universal feature of the phase transition in the experimental system and that the orientational ordering belongs to the KT universality class.Comment: 8 pages, 9 figure

NATO Survey of Mental Health Training in Army Recruits

To-date, there has been no international review of mental health resilience training during Basic Training nor an assessment of what service members perceive as useful from their perspective. In response to this knowledge gap, the North Atlantic Treaty Organization (NATO) Human Factors & Medicine Research & Technology Task Group “Mental Health Training” initiated a survey and interview with seven to twenty recruits from nine nations to inform the development of such training (N = 121). All nations provided data from soldiers joining the military as volunteers, whereas two nations also provided data from conscripts. Results from the volunteer data showed relatively consistent ranking in terms of perceived demands, coping strategies, and preferences for resilience skill training across the nations. Analysis of data from conscripts identified a select number of differences compared to volunteers. Subjects also provided examples of coping with stress during Basic Training that can be used in future training; themes are presented here. Results are designed to show the kinds of demands facing new recruits and coping methods used to overcome these demands to develop relevant resilience training for NATO nations

Critical behavior of Josephson-junction arrays at f=1/2

The critical behavior of frustrated Josephson-junction arrays at $f=1/2$ flux quantum per plaquette is considered. Results from Monte Carlo simulations and transfer matrix computations support the identification of the critical behavior of the square and triangular classical arrays and the one-dimensional quantum ladder with the universality class of the XY-Ising model. In the quantum ladder, the transition can happen either as a simultaneous ordering of the $Z_2$ and $U(1)$ order parameters or in two separate stages, depending on the ratio between interchain and intrachain Josephson couplings. For the classical arrays, weak random plaquette disorder acts like a random field and positional disorder as random bonds on the $Z_2$ variables. Increasing positional disorder decouples the $Z_2$ and $U(1)$ variables leading to the same critical behavior as for integer $f$.Comment: 9 pages, Latex, workshop on JJA, to appear in Physica

Complement activation during OKT3 treatment: A possible explanation for respiratory side effects

Complement activation during OKT3 treatment: A possible explanation for respiratory side effects. Respiratory side effects that sometimes occur during treatment with anti-CD3 MAb OKT3 might result from pulmonary sequestration of activated neutrophils. Therefore, we studied complement activation in relation to activation and pulmonary sequestration of neutrophils during antirejection treatment with OKT3. In each of nine patients studied, plasma C3a-desarg and C4b/c levels increased compared with pretreatment values already in the first sample taken 15 minutes after the first dose of OKT3 (P < 0.05), with peak values at 15 and 30 minutes, respectively. Levels of neutrophil degranulation product elastase (complexed to α1-antitrypsin) also increased already at 15 minutes after the first dose of OKT3 (P < 0.05), which is before elevated levels of the cytokines TNFα, IL-6 or IL-8 were detectable. In contrast, upon subsequent OKT3 administrations or in the control group treated with methylprednisolone, neither complement activation, cytokine release nor neutrophil degranulation occurred. In five studied patients treated with OKT3, pulmonary sequestration of radiolabeled granulocytes was observed from 3 until 15 minutes after the first dose of OKT3, together with peripheral blood granulocytopenia, which lasted at least 30 minutes. In conclusion, we demonstrate a simultaneous activation of complement and pulmonary sequestration of activated granulocytes immediately following the first dose of OKT3. These phenomena may be involved in the development of respiratory side effects complicating this therapy

Морфология и трехмерные изображения рудника-пещеры Кан-и-Гут

Путём сравнительного анализа и компьютерной обработки данных чертежей и схем из разных источников впервые получена пространственная (3D) модель одного из самых сложных в морфологическом отношении подземелий смешанного типа – рудника-пещеры Кан-и-Гут (Кыргызстан). Описана методика перевода графических данных в цифровой формат. Найдены основные морфометрические параметры полости, представлены трехмерные изображения основных его отделов, обсуждается их морфология. В ряде полостей рудника-пещеры выявлены существенные изменения, произошедшие за последние 50 лет вследствие масштабных обрушений.Шляхом порівняльного аналізу і комп’ютерної обробки даних креслень і схем з різних джерел вперше отримана просторова (3d) модель одного з найскладніших в морфологічному відношенні підземель змішаного типа – копальні-печери Кан-і-Гут (Киргизстан). Описана методика переведення графічних даних в цифровий формат. Знайдені основні морфометричні параметри порожнини, представлені тривимірні зображення основних його відділів, обговорюється їх морфологія. У ряді порожнин копальні-печери виявлені істотні зміни, події за останніх 50 років унаслідок масштабних обвалень.Kan-i-Gut mined cave, located in Kyrgyzstan, is one of the most morphologically complex cavities of mixed genesis. For the first time, a 3D model was developed for this cave by comparative analyses and computer processing of cave maps and mine surveyor plan and profile, obtained from different sources. The methodology of transferring graphical data into digital format is described. Primary morphometric parameters of the mined cave are gathered, and 3D images of its main parts are presented. Essential morphological changes due to vast collapses during the last 50 years were discovered